Pharmacological inhibition of IK1 by PA-6 in isolated rat hearts affects ventricular repolarization and refractoriness.

Mark A Skarsfeldt,Rikke Buhl,Chuyi Tang,Bo H Bentzen,Thomas Jespersen,Lasse Skibsbye,Helena Carstensen

doi:10.14814/phy2.12734

Mark A Skarsfeldt, Rikke Buhl + Show 5 more

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https://doi.org/10.14814/phy2.12734

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Journal: Physiological Reports	Publication Date: Apr 1, 2016
Citations: 26	License type: cc-by

Affiliation: University of Copenhagen

Abstract

The inwardly rectifying potassium current (IK 1) conducted through Kir2.X channels contribute to repolarization of the cardiac action potential and to stabilization of the resting membrane potential in cardiomyocytes. Our aim was to investigate the effect of the recently discovered IK 1 inhibitor PA‐6 on action potential repolarization and refractoriness in isolated rat hearts. Transiently transfected HEK‐293 cells expressing IK 1 were voltage‐clamped with ramp protocols. Langendorff‐perfused heart experiments were performed on male Sprague–Dawley rats, effective refractory period, Wenckebach cycle length, and ventricular effective refractory period were determined following 200 nmol/L PA‐6 perfusion. 200 nmol/L PA‐6 resulted in a significant time‐latency in drug effect on the IK 1 current expressed in HEK‐293 cells, giving rise to a maximal effect at 20 min. In the Langendorff‐perfused heart experiments, PA‐6 prolonged the ventricular action potential duration at 90% repolarization (from 41.8 ± 6.5 msec to 72.6 ± 21.1 msec, 74% compared to baseline, P < 0.01, n = 6). In parallel, PA‐6 significantly prolonged the ventricular effective refractory period compared to baseline (from 34.8 ± 4.6 msec to 58.1 ± 14.7 msec, 67%, P < 0.01, n = 6). PA‐6 increased the short‐term beat‐to‐beat variability and ventricular fibrillation was observed in two of six hearts. Neither atrial ERP nor duration of atrial fibrillation was altered following PA‐6 application. The results show that pharmacological inhibition of cardiac IK 1 affects ventricular action potential repolarization and refractoriness and increases the risk of ventricular arrhythmia in isolated rat hearts.

Highlights

The inward rectifier potassium current (IK1) contributes to repolarization in cardiomyocytes (Dhamoon and Jalife 2005). It is important for setting the diastolic membrane potential (Phase 4 of the cardiac action potential, named resting membrane potential), and for the late repolarization of the cardiac action potential (Phase 3) where it constitutes a part of the repolarization reserve currents (Ibarra et al 1991)
Because the PA-6 binding site on the Kir2.1 channel is located at the cytosolic part of the channel, the onset of current inhibition was slow when the drug was applied to the extracellular solution, as observed by De Boer a 2016 The Authors
To address the relative inhibition of the inward and outward potassium current following PA-6 inhibition current reduction was measured at À70 mV and À110 mV (Fig. 1C)

Summary

Introduction

The inward rectifier potassium current (IK1) contributes to repolarization in cardiomyocytes (Dhamoon and Jalife 2005). It is important for setting the diastolic membrane potential (Phase 4 of the cardiac action potential, named resting membrane potential), and for the late repolarization of the cardiac action potential (Phase 3) where it constitutes a part of the repolarization reserve currents (Ibarra et al 1991). Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society

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